Methods of Using C-Met Modulators

ABSTRACT

or a pharmaceutically acceptable salt or solvate thereof, in combination with other cancer treatments are described, wherein R1 is halo; R2 is halo; and Q is CH or N.

FIELD OF THE INVENTION

This invention relates to methods of using c-Met modulators, andspecifically c-Met modulators in combination with other anti-canceragents and/or radiation, which can be useful for the modulation ofvarious cellular activities and for the treatment of various diseases asdescribed in the specification.

BACKGROUND OF THE INVENTION

Traditionally, dramatic improvements in the treatment of cancer areassociated with identification of therapeutic agents acting throughnovel mechanisms. One mechanism that can be exploited in cancertreatment is the modulation of protein kinase activity because signaltransduction through protein kinase activation is responsible for manyof the characteristics of tumor cells. Protein kinase signaltransduction is of particular relevance in, for example, thyroid,gastric, head and neck, lung, breast, prostate, and colorectal cancers,as well as in the growth and proliferation of brain tumor cells.

Protein kinases can be categorized as receptor type or non-receptortype. Receptor-type tyrosine kinases are comprised of a large number oftransmembrane receptors with diverse biological activity. For a detaileddiscussion of the receptor-type tyrosine kinases, see Plowman et al.,DN&P 7(6): 334-339, 1994. Since protein kinases and their ligands playcritical roles in various cellular activities, deregulation of proteinkinase enzymatic activity can lead to altered cellular properties, suchas uncontrolled cell growth associated with cancer. In addition tooncological indications, altered kinase signaling is implicated innumerous other pathological diseases, including, for example,immunological disorders, cardiovascular diseases, inflammatory diseases,and degenerative diseases. Therefore, protein kinases are attractivetargets for small molecule drug discovery. Particularly attractivetargets for small-molecule modulation with respect to antiangiogenic andantiproliferative activity include receptor type tyrosine kinases Ret,c-Met, and VEGFR2.

The kinase c-Met is the prototypic member of a subfamily ofheterodimeric receptor tyrosine kinases (RTKs) which include Met, Ronand Sea. The endogenous ligand for c-Met is the hepatocyte growth factor(HGF), a potent inducer of angiogenisis. Binding of HGF to c-Met inducesactivation of the receptor via autophosphorylation resulting in anincrease of receptor dependent signaling, which promotes cell growth andinvasion. Anti-HGF antibodies or HGF antagonists have been shown toinhibit tumor metastasis in vivo (See: Maulik et al Cytokine & GrowthFactor Reviews 2002 13, 41-59). c-Met, VEGFR2 and/or Ret overexpressionhas been demonstrated on a wide variety of tumor types including breast,colon, renal, lung, squamous cell myeloid leukemia, hemangiomas,melanomas, astrocytomas, and glioblastomas. The Ret protein is atransmembrane receptor with tyrosine kinase activity. Ret is mutated inmost familial forms of medullary thyroid cancer. These mutationsactivate the kinase function of Ret and covert it into an oncogeneproduct.

Inhibition of EGF, VEGF and ephrin signal transduction will prevent cellproliferation and angiogenesis, two key cellular processes needed fortumor growth and survival (Matter A. Drug Disc. Technol. 20016,1005-1024). Kinase KDR (refers to kinase insert domain receptor tyrosinekinase) and flt-4 (fms-like tyrosine kinase-4) are both vascularendothelial growth factor (VEGF) receptors. Inhibition of EGF, VEGF andephrin signal transduction will prevent cell proliferation andangiogenesis, two key cellular processes needed for tumor growth andsurvival (Matter A. Drug Disc. Technol. 2001 6, 1005-1024). EGF and VEGFreceptors are desirable targets for small molecule inhibition.

Glioblastoma is the most aggressive form of primary brain tumor, with anincidence of 2.3 per 100,000 persons per year in the United States. Themedian survival time following diagnosis is 12-15 months with currentstandard of care involving surgery followed by radiation. It has beenreported that targeting the MET pathway potentiates GBM response togamma-radiation (Lal et al, 2005). It has also been report that METexpression correlate with high grade GBM tumors (Hirose et al, 1998) andexpression of HGF and MET correlate with malignancy (Koochekpour et al,1995; Abounader et al, 2001, Uchinokura et al, 2006). It has also beenreported that the glioma derived stem cell factor induces angiogenesiswithin the brain. SCF and VEGF may have complementary roles in therobust angiogenic response in GBM (Sun et al, 2006).

Accordingly, small-molecule compounds that specifically inhibit,regulate and/or modulate the signal transduction of kinases,particularly including Ret, c-Met and VEGFR2 described above, areparticularly desirable as a means to treat or prevent disease statesassociated with abnormal cell proliferation and angiogenesis. One suchsmall-molecule isN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,which has the chemical structure:

WO 2005/030140 describes the synthesis ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(Examples 25, 37, 38, and 48) and also discloses the therapeuticactivity of this molecule to inhibit, regulate and/or modulate thesignal transduction of kinases, (Assays, Table 4, entry 289). Compound(I) has been measured to have an c-Met IC₅₀ value of 1.3 nanomolar (nM)and a Ret IC₅₀ value of 5.2 nanomolar (nM).

Thus, finding new uses of compounds for treating diseases by using newcombination therapies is desirable.

SUMMARY OF THE INVENTION

The summary of the invention only summarizes certain aspects of theinvention and is not intended to be limiting in nature. These aspectsand other aspects and embodiments are described more fully below. Allreferences cited in this specification are hereby incorporated byreference in their entirety. In the event of a discrepancy between theexpress disclosure of this specification and the references incorporatedby reference, the express disclosure of this specification shallcontrol.

One aspect of this disclosure relates to methods of treating diseases,as defined in the detailed description herein below. These methods oftreatment include administering a Compound of Formula I, wherein thecompound of Formula I is as define in the detailed description of theinvention, to a patient in need of the treatment, in combination witheither temozolomide (TMZ) and/or radiation therapy (RT) and optionallyone or more additional treatment(s), wherein the one or more additionaltreatment(s) are as described in the detailed description of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

Aspect (I) of this disclosure relates to a method of treating a diseasecomprising administering to a patient in need of the treatment acompound of Formula I:

or a pharmaceutically acceptable salt thereof, in combination withtemozolomide (TMZ) wherein:R¹ is halo;R² is halo; and

Q is CH or N.

Aspect (II) of this disclosure relates to a method of treating a diseasecomprising administering to a patient in need of the treatment acompound of Formula I:

or a pharmaceutically acceptable salt thereof, in combination withradiation therapy (RT) wherein:R¹ is halo;R² is halo; and

Q is CH or N.

In other embodiments of aspect (I) and Aspect (II) of this disclosurethe compound of Formula I, or a pharmaceutically acceptable saltthereof, is a pharmaceutical composition which further comprises apharmaceutically acceptable carrier, excipient, or diluent.

In other embodiments of Aspect (I), the method further comprisesadministereing to the patient one or more additional treatment(s),wherein the one or more treatment(s) are selected from (1) surgery, (2)one or more additional chemotherapeutic agent(s), (3) one or morehormone therapy(s), (4) one or more antibody(s), and (5) one or moreimmunotherapy(ies), (6) radioactive iodine therapy, and (7) radiation.

In other embodiments of Aspect (II), the method further comprisesadministering to the patient one or more additional treatment(s),wherein the one or more treatment(s) are selected from (1) surgery, (2)one or more additional chemotherapeutic agent(s), (3) one or morehormone therapy(s), (4) one or more antibody(s), and (5) one or moreimmunotherapy(ies).

In other embodiments of Aspect (I) and Aspect (II), the compound ofFormula I in any of the above embodiments is the following compound:

or a pharmaceutical salt thereof.

In other embodiments of Aspect (I) and Aspect (II), the compound ofFormula I in any of the above embodiments is the following compound:

The compound of Formula (I), and all of the embodiments of the compoundof Formula (I) as described herein, includes both the recited compoundsas well as individual isomers and mixtures of isomers. In each instance,the compound of Formula (I) includes the pharmaceutically acceptablesalts, hydrates, and/or solvates of the recited compounds and anyindividual isomers or mixture of isomers thereof.

Abbreviations and Definitions

The following abbreviations and terms have the indicated meaningsthroughout:

Abbreviation Meaning Ac acetyl Br broad ° C. degrees Celsius c- cycloCBZ CarboBenZoxy = benzyloxycarbonyl d doublet dd doublet of doublet dtdoublet of triplet DCM dichloromethane DME 1,2-dimethoxyethane DMFN,N-dimethylformamide DMSO dimethyl sulfoxide dppf1,1′-bis(diphenylphosphano)ferrocene EI Electron Impact ionization ggram(s) Gy Gray unit h or hr hour(s) HPLC high pressure liquidchromatography L liter(s) M molar or molarity m Multiplet mgmilligram(s) MGMT O⁶-Methylguanine methyltransferase MHz megahertz(frequency) Min minute(s) mL milliliter(s) μL microliter(s) μMMicromole(s) or micromolar mM Millimolar mmol millimole(s) mol mole(s)MS mass spectral analysis N normal or normality nM Nanomolar NMR nuclearmagnetic resonance spectroscopy q Quartet RT Radiation Therapy s Singlett or tr Triplet TFA trifluoroacetic acid THF tetrahydrofuran TLC thinlayer chromatography

The symbol “-” means a single bond, “=” means a double bond.

When chemical structures are depicted or described, unless explicitlystated otherwise, all carbons are assumed to have hydrogen substitutionto conform to a valence of four. For example, in the structure on theleft-hand side of the schematic below there are nine hydrogens implied.The nine hydrogens are depicted in the right-hand structure. Sometimes aparticular atom in a structure is described in textual formula as havinga hydrogen or hydrogens as substitution (expressly defined hydrogen),for example, —CH₂CH₂—. It is understood by one of ordinary skill in theart that the aforementioned descriptive techniques are common in thechemical arts to provide brevity and simplicity to description ofotherwise complex structures.

If a group “R” is depicted as “floating” on a ring system, as forexample in the formula:

then, unless otherwise defined, a substituent “R” may reside on any atomof the ring system, assuming replacement of a depicted, implied, orexpressly defined hydrogen from one of the ring atoms, so long as astable structure is formed.

If a group “R” is depicted as floating on a fused ring system, as forexample in the formulae:

then, unless otherwise defined, a substituent “R” may reside on any atomof the fused ring system, assuming replacement of a depicted hydrogen(for example the —NH— in the formula above), implied hydrogen (forexample as in the formula above, where the hydrogens are not shown butunderstood to be present), or expressly defined hydrogen (for examplewhere in the formula above, “Z” equals ═CH—) from one of the ring atoms,so long as a stable structure is formed. In the example depicted, the“R” group may reside on either the 5-membered or the 6-membered ring ofthe fused ring system. In the formulas depicted above, there may morethan one R group (R_(y)), wherein y is an integer of 1 or more. When yis 2, for example, then the two “R's” may reside on any two atoms of thering system, again assuming each replaces a depicted, implied, orexpressly defined hydrogen on the ring.

When a group “R” is depicted as existing on a ring system containingsaturated carbons, as for example in the formula:

where, in this example, “y” can be more than one, assuming each replacesa currently depicted, implied, or expressly defined hydrogen on thering; then, unless otherwise defined, where the resulting structure isstable, two “R's” may reside on the same carbon. A simple example iswhen R is a methyl group; there can exist a geminal dimethyl on a carbonof the depicted ring (an “annular” carbon). In another example, two R'son the same carbon, including that carbon, may form a ring, thuscreating a spirocyclic ring (a “spirocyclyl” group) structure with thedepicted ring as for example in the formula:

“Halogen” or “halo” refers to fluorine, chlorine, bromine or iodine.

“Yield” for each of the reactions described herein is expressed as apercentage of the theoretical yield.

“Cancer” refers to cellular-proliferative disease states, including butnot limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma,rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma andteratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiatedsmall cell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma,chondromatous hanlartoma, inesothelioma; Gastrointestinal: esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinorna, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma,fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma,Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma,hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone:osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors; Nervous system: skull (osteoma, hemangioma,granuloma, xanthoma, osteitis defornians), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma [pinealoma], glioblastorna multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological:uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma [serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma], fallopian tubes (carcinoma); Hematologic:blood (myeloid leukemia [acute and chronic], acute lymphoblasticleukemia, chronic lymphocytic leukemia, myeloproliferative diseases,multiple myeloma, myelodysplastic syndrome), Hodgkin's disease,non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma,basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis;Adrenal Glands: neuroblastoma; and breast cancer. Thus, the term“cancerous cell” as provided herein, includes a cell afflicted by anyone of the above-identified conditions.

“Hormone therapy” or “hormonal therapy” includes, for example, treatmentwith one or more of the following: steroids (e.g. dexamethasone),finasteride, tamoxifen, and an aromatase inhibitor.

“Patient” for the purposes of the present invention includes humans andother animals, particularly mammals, and other organisms. Thus themethods are applicable to both human therapy and veterinaryapplications. In another embodiment the patient is a mammal, and inanother embodiment the patient is human.

A “pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. It is understood thatthe pharmaceutically acceptable salts are non-toxic. Additionalinformation on suitable pharmaceutically acceptable salts can be foundin Remington's Pharmaceutical Sciences, 17^(th) ed., Mack PublishingCompany, Easton, Pa., 1985, which is incorporated herein by reference orS. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977;66:1-19 both of which are incorporated herein by reference.

Examples of pharmaceutically acceptable acid addition salts includethose formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, and the like; as wellas organic acids such as acetic acid, trifluoroacetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonicacid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, p-toluenesulfonic acid, and salicylicacid and the like.

Examples of a pharmaceutically acceptable base addition salts includethose formed when an acidic proton present in the parent compound isreplaced by a metal ion, such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Specific salts are the ammonium, potassium, sodium, calcium,and magnesium salts. Salts derived from pharmaceutically acceptableorganic non-toxic bases include, but are not limited to, salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins. Examples of organic bases include isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, tromethamine, N-methylglucamine, polyamine resins,and the like. Exemplary organic bases are isopropylamine, diethylamine,ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

“Platin(s),” and “platin-containing agent(s)” include, for example,cisplatin, carboplatin, and oxaliplatin.

“Prodrug” refers to compounds that are transformed (typically rapidly)in vivo to yield the parent compound of the above formulae, for example,by hydrolysis in blood. Common examples include, but are not limited to,ester and amide forms of a compound having an active form bearing acarboxylic acid moiety. Examples of pharmaceutically acceptable estersof the compounds of this invention include, but are not limited to,alkyl esters (for example with between about one and about six carbons)the alkyl group is a straight or branched chain. Acceptable esters alsoinclude cycloalkyl esters and arylalkyl esters such as, but not limitedto benzyl. Examples of pharmaceutically acceptable amides of thecompounds of this invention include, but are not limited to, primaryamides, and secondary and tertiary alkyl amides (for example withbetween about one and about six carbons). Amides and esters of thecompounds of the present invention may be prepared according toconventional methods. A thorough discussion of prodrugs is provided inT. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein by referencefor all purposes.

“Taxane(s)” includes, for example, one or more of the following:Paclitaxel (Taxol®) and Docetaxel (Taxotere®).

“Therapeutically effective amount” is an amount of a compound of theinvention, that when administered to a patient, ameliorates a symptom ofthe disease. A therapeutically effective amount is intended to includean amount of a compound alone or in combination with other activeingredients effective to modulate Ret, c-Met, and/or VEGFR2, oreffective to treat or prevent cancer. The amount of a compound of theinvention which constitutes a “therapeutically effective amount” willvary depending on the compound, the disease state and its severity, theage of the patient to be treated, and the like. The therapeuticallyeffective amount can be determined routinely by one of ordinary skill inthe art having regard to their knowledge and to this disclosure.

“Topoisomerase inhibitor” includes, for example, one or more of thefollowing: amsacrine, camptothecin, etoposide, etoposide phosphate,exatecan, irinotecan, lurtotecan, and teniposide, and topotecan.

“Treating” or “treatment” of a disease, disorder, or syndrome, as usedherein, includes (i) preventing the disease, disorder, or syndrome fromoccurring in a human, i.e. causing the clinical symptoms of the disease,disorder, or syndrome not to develop in an animal that may be exposed toor predisposed to the disease, disorder, or syndrome but does not yetexperience or display symptoms of the disease, disorder, or syndrome;(ii) inhibiting the disease, disorder, or syndrome, i.e., arresting itsdevelopment; and (iii) relieving the disease, disorder, or syndrome,i.e., causing regression of the disease, disorder, or syndrome. As isknown in the art, adjustments for systemic versus localized delivery,age, body weight, general health, sex, diet, time of administration,drug interaction and the severity of the condition may be necessary, andwill be ascertainable with routine experimentation by one of ordinaryskill in the art.

Additional Embodiments of the Invention

In another embodiment of Aspect (I) or Aspect (II) of this disclosure,the disease being treated is selected from astocytoma, glioblastoma,giant cell glioblastoma, gliosarcoma, and glioblastoma witholigodendroglial components.

In another embodiment of Aspect (I) of this disclosure, the methodfurther comprises administering radiation therapy to the patient.

In another embodiment of Aspect (I) of this disclosure, the disease isselected from astocytoma, glioblastoma, giant cell glioblastoma,gliosarcoma, and glioblastoma with oligodendrogilial components; and thethe method further comprises administering radiation therapy to thepatient.

In another embodiment of Aspect (I) or Aspect (II) of this disclosure,the disease is selected from astocytoma, glioblastoma, giant cellglioblastoma, gliosarcoma, and glioblastoma with oligodendrogilialcomponents; and the the method further comprises administering surguryto the patient.

In another embodiment of Aspect (I) of this disclosure, the disease isselected from astocytoma, glioblastoma, giant cell glioblastoma,gliosarcoma, and glioblastoma with oligodendrogilial components; and thethe method further comprises administering radiation therapy and surgeryto the patient.

Non-limiting examples of the additional chemotherapeutic agent(s) thatcan be used in any of the above embodiments include rapamycin, arapamycin analogue, an alkylating agent(s), a taxane(s), and aplatin(s). In chemotherapeutic agent(s) is selected from rapamycin,temozolomide, paclitaxel, docetaxel, carboplatin, cisplatin,oxaliplatin, gefitinib (Iressa®), erlotinib (Tarceva®), Zactima(ZD6474), HKI-272, pelitinib, canertinib, and lapatinib.

A non-limiting example of the antibody that can be used as the one ormore additional treatments in Aspect (I) or Aspect (II) of thisdisclosure is panitumumab.

In another embodiment of Aspect (I) or (II) of this disclosure, the oneor more additional treatments is one or more hormone therapy(s).Non-limiting examples of the hormone therapy(s) that can be used in thisembodiment include tamoxifen, Toremifene (Fareston), Fulvestrant(Faslodex), Megestrol acetate (Megace), ovarian ablation, Raloxifene, aluteinizing hormone-releasing hormone (LHRH) analog (including goserelinand leuprolide), Megestrol acetate (Megace), and one or more aromataseinhibitor(s); in another embodiment, one or more of the aromataseinhibitor(s) is selected from letrozole (Femara), anastrozole(Arimidex), and exemestane (Aromasin). In another embodiment, one ormore of the hormone therapy(s) is selected from tamoxifen and anaromatase inhibitor.

In another embodiment of Aspect (I) or Aspect (II) of this disclosure,the disease is an astrocytic tumor selected from astocytoma,glioblastoma, giant cell glioblastoma, gliosarcoma, and glioblastomawith oligodendroglial components, and the one or more treatment(s) areselected from (1) surgery, (2) radiation, (3) one or more additionalchemotherapeutic agent(s), (4) one or more anti-seizure agent(s), and(5) one or more agent(s) to reduce swelling. Non-limiting examples ofthe radiation treatment that can be used in this embodiment includeexternal beam radiation, interstitial radiotherapy, and stereotacticradiosurgery. Non-limiting examples of the additional chemotherapeuticagent(s) that can be used in this embodiment include carmustine (BCNU),Erlotinib (Tarceva), bevacizumab, gefitinib (Iressa), rapamycin,cisplatin, BCNU, lomustine, procarbazine, and vincristine. Anon-limiting examples of the antiseizure agent(s) that can be used inthis embodiment is diphenylhydantoin (Dilantin). A non-limiting exampleof the agent that can be used to reduce swelling in this embodimentinclude dexamethasone (Decadron).

In another embodiment of Aspect (I) of this disclosure, the one or moreadditional treatments are radiation and surgery.

In another embodiment of Aspect (I) of this disclosure, the one or moreadditional treatments are radiation and one or more additionalchemotherapeutic agent(s).

In another embodiment of Aspect (I) or Aspect (II) of this disclosure,the one or more additional treatments are surgery and one or moreadditional chemotherapeutic agent(s).

In another embodiment, treatment for patients with GB comprises a (1)“concurrent phase,” which is followed by a (2) “rest phase,” which isfollowed by a (3) “maintenance phase.”

The concurrent phase is followed by a (2) “rest phase which can rangefrom about 2 weeks to about 8 weeks in duration. The rest phase is meantto allow for recovery from delayed toxicity, if present. In anotherembodiment, the rest phase can range from about 3 weeks to about 6 weeksin duration. In another embodiment, the rest phase is about 4 weeks induration.

The rest phase is followed by a (3) “maintenance phase,” during whichpatients receive active pharmaceutical ingredients for approximatelytwelve 28-day cycles, but can vary from about six to about twenty four28-day cycles. In various embodiments, patients receive differentamounts of the compound of Formula I at different times according to thephase of TMZ and radiation therapy.

Concurrent Phase

During the concurrent phase, the compound of Formula I, in oneembodiment, can be administered to the patient concurrently with RT andTMZ for 3-12 weeks, or 4-10 weeks, or 6-7 weeks. In another embodiment,for patients having a mutation in the MGMT promoter wherein the mutatedMGMT promoter is an unmethylated promoter, the compound of Formula Iwill be administered to the patient concurrently with RT for 6-7 weeksin the concurrent phase. The concurrent phase can range from about 3weeks to about 12 weeks in duration. In another embodiment, theconcurrent phase ranges from about 4 weeks to about 10 weeks induration. In another embodiment, the concurrent phase ranges from about6 weeks to about 8 weeks in duration. In another embodiment, theconcurrent phase ranges from about 6 weeks to about 7 weeks in duration.During the concurrent phase, active pharmaceutical ingredients are givenwith (RT). In another embodiment, the active pharmaceuticalingredient(s) in the concurrent phase are TMZ and the compound ofFormula I. In another embodiment, the active pharmaceutical ingredientin the concurrent phase is TMZ provided that the compound of Formula Iis at least one of the active pharmaceutical ingredients in themaintenance phase. In another embodiment, the active pharmaceuticalingredient in the concurrent phase is the compound of Formula I.

Rest Phase

During the rest phase, no RT, compounds of Formula I, or TMZ isadministered to the patient. The rest phase can range from about 2 weeksto about 12 weeks. In another embodiment, the rest phase can range fromabout 3 weeks to about 6 weeks in duration. In another embodiment, therest phase range is about 4 weeks in duration.

Maintenance Phase

In one embodiment of the maintenance phase, the compound of Formula I isadministered to the patient. In another embodiment of the maintenancephase, temozolomide and the compound of Formula I are both administeredto the patient. In another embodiment of the maintenance phase,temozolomide and the compound of Formula I are each administered to thepatient for a period of time ranging from about 4 months to about 10months. In another embodiment of the maintenance phase, temozolomide andthe compound of Formula I are each administered to the patient for about4 months. In another embodiment of the maintenance phase, temozolomideand the compound of Formula I are each administered to the patient forabout 5 months. In another embodiment of the maintenance phase,temozolomide and the compound of Formula I are each administered to thepatient for about 6 months. In another embodiment of the maintenancephase, temozolomide and the compound of Formula I are each administeredto the patient for about 7 months. In another embodiment of themaintenance phase, temozolomide and the compound of Formula I are eachadministered to the patient for about 8 months. In another embodiment ofthe maintenance phase, temozolomide and the compound of Formula I areeach administered to the patient for about 9 months. In anotherembodiment of the maintenance phase, temozolomide and the compound ofFormula I are each administered to the patient for about 10 months. Inanother embodiment of the maintenance phase, the compound of Formula Iis administered to the patient for period of time ranging from about 4months to about 10 months. In another embodiment of the maintenancephase, the compound of Formula I is administered for about 4 months. Inanother embodiment of the maintenance phase, the compound of Formula Iis administered for about 5 months. In another embodiment of themaintenance phase, the compound of Formula I is administered for about 6months. In another embodiment of the maintenance phase, the compound ofFormula I is administered for about 7 months. In another embodiment ofthe maintenance phase, the compound of Formula I is administered forabout 8 months. In another embodiment of the maintenance phase thecompound of Formula I is administered for about 9 months. In anotherembodiment of the maintenance phase, the compound of Formula I isadministered for 10 months.

During the maintenance phase, the compound of Formula I can beadministered daily as a single oral agent as a 10-200 mg dosages (whichcan be in capsules or tablets). In another embodiment of the maintenancephase, the compound of Formula I can be administered daily as a singleoral agent as a 25-125 mg dosage, or 25-100 mg dosage, (which can be ina capsule or tablet). Also during the maintenance phase, TMZ can beadministered for 5 consecutive days and repeated every 28 days. TMZ,during the maintenance phase, can be administered to the patient as5-300 mg dosages (which can be in capsules or tablets) to the patient.

For purposes of this disclosure, for all examples that are disclosedherein that refer to the compound of Formula I or temozolomide in dosageamounts in milligrams (mg), it is to be read as mg of the compound inquestion, and this dosage amount can be administered in any form,including tablet and capsule form. The examples of capsule or tabletforms, that are within the parenthesis after the dosage amounts, arenon-limiting examples of how the dosages can be administered and theseexamples are meant to be non-limiting. For example, in the aboveembodiment, TMZ can be administered in other modes in addition tocapsules or tablets, which are meant to be only non-limiting examples ofhow the dosage amount can be administered.

In non-limiting examples in all of the above embodiments (including theconcurrent and maintenance phases), the compound of Formula I can beadministered in 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg,45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185mg, 190 mg, 195 mg, and 200 mg dosages (which can be in capsules ortablets).

In non-limiting examples in all of the above embodiments (including theconcurrent and maintenance phases), TMZ can be administered in 5 mg, 10mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245mg, 250 mg, 255 mg, 260 mg, 265 mg, 260 mg, 275 mg, 280 mg, 285 mg, 290mg, 295 mg, and 300 mg dosages (which can be in capsules or tablets).

In another embodiment of Aspect (I) or Aspect (II) of this disclosure,the concurrent phase comprises administering radiation and the compoundof Formula I to the patient; the rest phase comprises not administeringthe compound of Formula I or radiation to the patient; and themaintenance phase comprises administering the compound of Formula I tothe patient. In one subembodiment of this embodiment, the concurrentphase can be 7-8 weeks in duration, the rest phase can be about 4 weeksin duration; and the maintenance phase is of a duration sufficient slowdown the cancer growth. In another subembodiment of this embodiment, thecompound of Formula I is administered to the patient in 25-100 mgdosages, or 25-125 mg dosages, (which can be in capsules or tablets)daily during the concurrent phase; TMZ is administered to the patient in5-180 mg dosages (which can be in capsules or tablets) daily to thepatient during the concurrent phase; RT is administered to the patientduring the concurrent phase using 1.8-2 Gy/fraction, daily for 5days/week for a total dose of up to 60 Gy; the compound of Formula I isadministered to the patient in 25-100 mg dosages, or 25-125 mg dosages,(which can be in capsules or tablets) daily during the maintenancephase; and TMZ is administered to the patient in 5-180 mg dosages (whichcan be in capsules or tablets) for 5 consecutive days and repeated every28 days until the cancer growth is slowed down.

In other embodiments of any of the above embodiments of Aspect (I) andAspect (II), the Compound of Formula I is the following compound:

or a pharmaceutical salt thereof.

In another embodiment, the compound of Formula I is the (L)-malate saltform ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamidehaving the following structure:

General Administration

In one aspect, the invention provides pharmaceutical compositionscomprising a compound of Formula I as described above and apharmaceutically acceptable carrier, excipient, or diluent. In certainother embodiments, administration is by the oral route. Administrationof the compound of Formula I, or their pharmaceutically acceptablesalts, in pure form or in an appropriate pharmaceutical composition, canbe carried out via any of the accepted modes of administration or agentsfor serving similar utilities. Thus, administration can be, for example,orally, nasally, parenterally (intravenous, intramuscular, orsubcutaneous), topically, transdermally, intravaginally, intravesically,intracistemally, or rectally, in the form of solid, semi-solid,lyophilized powder, or liquid dosage forms, such as for example,tablets, suppositories, pills, soft elastic and hard gelatin dosages(which can be in capsules or tablets), powders, solutions, suspensions,or aerosols, or the like, specifically in unit dosage forms suitable forsimple administration of precise dosages.

The compositions will include a conventional pharmaceutical carrier orexcipient and a compound of Formula I as the/an active agent, and, inaddition, may include carriers and adjuvants, etc.

Adjuvants include preserving, wetting, suspending, sweetening,flavoring, perfuming, emulsifying, and dispensing agents. Prevention ofthe action of microorganisms can be ensured by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, and the like. It may also be desirable to include isotonic agents,for example sugars, sodium chloride, and the like. Prolonged absorptionof the injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

If desired, a pharmaceutical composition of the compound of Formula Imay also contain minor amounts of auxiliary substances such as wettingor emulsifying agents, pH buffering agents, antioxidants, and the like,such as, for example, citric acid, sorbitan monolaurate, triethanolamineoleate, butylated hydroxytoluene, etc.

The choice of formulation depends on various factors such as the mode ofdrug administration (e.g., for oral administration, formulations in theform of tablets, pills or capsules) and the bioavailability of the drugsubstance. Recently, pharmaceutical formulations have been developedespecially for drugs that show poor bioavailability based upon theprinciple that bioavailability can be increased by increasing thesurface area i.e., decreasing particle size. For example, U.S. Pat. No.4,107,288 describes a pharmaceutical formulation having particles in thesize range from 10 to 1,000 nm in which the active material is supportedon a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684describes the production of a pharmaceutical formulation in which thedrug substance is pulverized to nanoparticles (average particle size of400 nm) in the presence of a surface modifier and then dispersed in aliquid medium to give a pharmaceutical formulation that exhibitsremarkably high bioavailability.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate. Proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions and by the use of surfactants.

One specific route of administration is oral, using a convenient dailydosage regimen that can be adjusted according to the degree of severityof the disease-state to be treated.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is admixed with at least one inert customary excipient (orcarrier) such as sodium citrate or dicalcium phosphate or (a) fillers orextenders, as for example, starches, lactose, sucrose, glucose,mannitol, and silicic acid, (b) binders, as for example, cellulosederivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose,and gum acacia, (c) humectants, as for example, glycerol, (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, croscarmellose sodium, complexsilicates, and sodium carbonate, (e) solution retarders, as for exampleparaffin, (f) absorption accelerators, as for example, quaternaryammonium compounds, (g) wetting agents, as for example, cetyl alcohol,and glycerol monostearate, magnesium stearate and the like (h)adsorbents, as for example, kaolin and bentonite, and (i) lubricants, asfor example, talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In thecase of capsules, tablets, and pills, the dosage forms may also comprisebuffering agents.

Solid dosage forms as described above can be prepared with coatings andshells, such as enteric coatings and others well known in the art. Theymay contain pacifying agents, and can also be of such composition thatthey release the active compound or compounds in a certain part of theintestinal tract in a delayed manner. Examples of embedded compositionsthat can be used are polymeric substances and waxes. The activecompounds can also be in microencapsulated form, if appropriate, withone or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Suchdosage forms are prepared, for example, by dissolving, dispersing, etc.,the compound of Formula I, or a pharmaceutically acceptable saltthereof, and optional pharmaceutical adjuvants in a carrier, such as,for example, water, saline, aqueous dextrose, glycerol, ethanol and thelike; solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,dimethylformamide; oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters ofsorbitan; or mixtures of these substances, and the like, to thereby forma solution or suspension.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Compositions for rectal administrations are, for example, suppositoriesthat can be prepared by mixing the compound of Formula I with, forexample, suitable non-irritating excipients or carriers such as cocoabutter, polyethyleneglycol or a suppository wax, which are solid atordinary temperatures but liquid at body temperature and therefore, meltwhile in a suitable body cavity and release the active componenttherein.

Dosage forms for topical administration of the compound of Formula Iinclude ointments, powders, sprays, and inhalants. The active componentis admixed under sterile conditions with a physiologically acceptablecarrier and any preservatives, buffers, or propellants as may berequired. Ophthalmic formulations, eye ointments, powders, and solutionsare also contemplated as being within the scope of this disclosure.

Compressed gases may be used to disperse the compound of Formula I inaerosol form. Inert gases suitable for this purpose are nitrogen, carbondioxide, etc.

Generally, depending on the intended mode of administration, thepharmaceutically acceptable compositions will contain about 1% to about99% by weight of a compound(s) of Formula I, or a pharmaceuticallyacceptable salt thereof, and 99% to 1% by weight of a suitablepharmaceutical excipient. In one example, the composition will bebetween about 5% and about 75% by weight of a compound(s) of Formula I,or a pharmaceutically acceptable salt thereof, with the rest beingsuitable pharmaceutical excipients.

Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton,Pa., 1990). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of Formula I,or a pharmaceutically acceptable salt thereof, for treatment of adisease-state in accordance with the teachings of this disclosure.

The compounds of this disclosure, or their pharmaceutically acceptablesalts or solvates, are administered in a therapeutically effectiveamount which will vary depending upon a variety of factors including theactivity of the specific compound employed, the metabolic stability andlength of action of the compound, the age, body weight, general health,sex, diet, mode and time of administration, rate of excretion, drugcombination, the severity of the particular disease-states, and the hostundergoing therapy. The compound of Formula I can be administered to apatient at dosage levels in the range of about 0.1 to about 1,000 mg perday. For a normal human adult having a body weight of about 70kilograms, a dosage in the range of about 0.01 to about 100 mg perkilogram of body weight per day is an example. The specific dosage used,however, can vary. For example, the dosage can depend on a number offactors including the requirements of the patient, the severity of thecondition being treated, and the pharmacological activity of thecompound being used. The determination of optimum dosages for aparticular patient is well known to one of ordinary skill in the art.

If formulated as a fixed dose, such combination products employ thecompound of Formula I within the dosage range described above and theother pharmaceutically active agent(s) within its approved dosage range.Compounds of Formula I may alternatively be used sequentially with knownpharmaceutically acceptable agent(s) when a combination formulation isinappropriate.

General Synthesis

Compounds of this invention can be made by the synthetic proceduresdescribed below. These procedures are merely illustrative of somemethods by which the compounds of Formula I can be synthesized, andvarious modifications to these procedures can be made. The startingmaterials and the intermediates of the reaction may be isolated andpurified if desired using conventional techniques, including but notlimited to filtration, distillation, crystallization, chromatography andthe like. Such materials may be characterized using conventional means,including physical constants and spectral data.

The disclosure is further illustrated by the following examples, whichare not to be construed as limiting the disclosure in scope or spirit tothe specific procedures described in them.

EXAMPLES Example 1A Preparation ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideand the (L)-malate salt thereof

A synthetic route that has been used for the preparation ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideand the (L)-malate salt thereof is depicted in FIG. 1:

The process above is described in more detail below.

Preparation of 4-Chloro-6,7-dimethoxy-quinoline

A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol(10.0 kg) and acetonitrile (64.0 L). The resulting mixture was heated toapproximately 65° C. and phosphorus oxychloride (POCl₃, 50.0 kg) wasadded. After the addition of POCl₃, the temperature of the reactionmixture was raised to approximately 80° C. The reaction was deemedcomplete (approximately 9.0 hours) when <2% of the starting materialremained (in process high-performance liquid chromotography [HPLC]analysis). The reaction mixture was cooled to approximately 10° C. andthen quenched into a chilled solution of dichloromethane (DCM, 238.0kg), 30% NH₄OH (135.0 kg), and ice (440.0 kg). The resulting mixture waswarmed to approximately 14° C., and phases were separated. The organicphase was washed with water (40.0 kg) and concentrated by vacuumdistillation with the removal of solvent (approximately 190.0 kg).Methyl-t-butyl ether (MTBE, 50.0 kg) was added to the batch, and themixture was cooled to approximately 10° C., during which time theproduct crystallized out. The solids were recovered by centrifugation,washed with n heptane (20.0 kg), and dried at approximately 40° C. toafford the title compound (8.0 kg).

Preparation of 6,7-dimethyl-4-(4-nitro-phenoxy)-quinoline

A reactor was sequentially charged with 4-chloro-6,7-dimethoxy-quinoline(8.0 kg), 4 nitrophenol (7.0 kg), 4 dimethylaminopyridine (0.9 kg), and2,6 lutidine (40.0 kg). The reactor contents were heated toapproximately 147° C. When the reaction was complete (<5% startingmaterial remaining as determined by in process HPLC analysis,approximately 20 hours), the reactor contents were allowed to cool toapproximately 25° C. Methanol (26.0 kg) was added, followed by potassiumcarbonate (3.0 kg) dissolved in water (50.0 kg). The reactor contentswere stirred for approximately 2 hours. The resulting solid precipitatewas filtered, washed with water (67.0 kg), and dried at 25° C. forapproximately 12 hours to afford the title compound (4.0 kg).

Preparation of 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine

A solution containing potassium formate (5.0 kg), formic acid (3.0 kg),and water (16.0 kg) was added to a mixture of6,7-dimethoxy-4-(4-nitro-phenoxy)-quinoline (4.0 kg), 10% palladium oncarbon (50% water wet, 0.4 kg) in tetrahydrofuran (40.0 kg) that hadbeen heated to approximately 60° C. The addition was carried out suchthat the temperature of the reaction mixture remained approximately 60°C. When the reaction was deemed complete as determined using in-processHPLC analysis (<2% starting material remaining, typically 15 hours), thereactor contents were filtered. The filtrate was concentrated by vacuumdistillation at approximately 35° C. to half of its original volume,which resulted in the precipitation of the product. The product wasrecovered by filtration, washed with water (12.0 kg), and dried undervacuum at approximately 50° C. to afford the title compound (3.0 kg).

Preparation of 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid

Triethylamine (8.0 kg) was added to a cooled (approximately 4C) solutionof commercially available cyclopropane-1,1-dicarboxylic acid (2 l, 10.0kg) in THF (63.0 kg) at a rate such that the batch temperature did notexceed 10° C. The solution was stirred for approximately 30 minutes, andthen thionyl chloride (9.0 kg) was added, keeping the batch temperaturebelow 10° C. When the addition was complete, a solution of4-fluoroaniline (9.0 kg) in THF (25.0 kg) was added at a rate such thatthe batch temperature did not exceed 10° C. The mixture was stirred forapproximately 4 hours and then diluted with isopropyl acetate (87.0 kg).This solution was washed sequentially with aqueous sodium hydroxide (2.0kg dissolved in 50.0 L of water), water (40.0 L), and aqueous sodiumchloride (10.0 kg dissolved in 40.0 L of water). The organic solutionwas concentrated by vacuum distillation followed by the addition ofheptane, which resulted in the precipitation of solid. The solid wasrecovered by centrifugation and then dried at approximately 35° C. undervacuum to afford the title compound. (10.0 kg).

Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonylchloride

Oxalyl chloride (1.0 kg) was added to a solution of1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (2.0 kg) in amixture of THE (11 kg) and N, N-dimethylformamide (DMF; 0.02 kg) at arate such that the batch temperature did not exceed 30° C. This solutionwas used in the next step without further processing.

Preparation ofN-(4-{[67-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

The solution from the previous step containing1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride was added toa mixture of 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (3.0 kg)and potassium carbonate (4.0 kg) in THF (27.0 kg) and water (13.0 kg) ata rate such that the batch temperature did not exceed 30° C. When thereaction was complete (in typically 10 minutes), water (74.0 kg) wasadded. The mixture was stirred at 15-30° C. for approximately 10 hours,which resulted in the precipitation of the product. The product wasrecovered by filtration, washed with a pre made solution of THE (11.0kg) and water (24.0 kg), and dried at approximately 65° C. under vacuumfor approximately 12 hours to afford the title compound (free base, 5.0kg). ¹H NMR (400 MHz, d₆-DMSO): δ 10.2 (s, 1H), 10.05 (s, 1H), 8.4 (s,1H), 7.8 (m, 2H), 7.65 (m, 2H), 7.5 (s, 1H), 7.35 (s, 1H), 7.25 (m, 2H),7.15 (m, 2H), 6.4 (s, 1H), 4.0 (d, 6H), 1.5 (s, 4H). LC/MS: M+H=502.

Preparation ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(L) malate salt

A solution of L-malic acid (2.0 kg) in water (2.0 kg) was added to asolution of cyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide free base (15, 5.0 kg) in ethanol, maintaining abatch temperature of approximately 25° C. Carbon (0.5 kg) and thiolsilica (0.1 kg) were then added, and the resulting mixture was heated toapproximately 78° C., at which point water (6.0 kg) was added. Thereaction mixture was then filtered, followed by the addition ofisopropanol (38.0 kg), and was allowed to cool to approximately 25° C.The product was recovered by filtration and washed with isopropanol(20.0 kg) and dried at approximately 65° C. to afford the title compound(5.0 kg).

Example 1B Preparation ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideand the (L)-malate salt thereof

Another synthetic route that has been used for the preparation ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideand the (L)-malate salt thereof is depicted in FIG. 2:

Preparation of 4-Chloro-6,7-dimethoxy-quinoline

A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol(47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heatedto approximately 60° C. and phosphorus oxychloride (POCl₃, 130.6 kg) wasadded. After the addition of POCl₃, the temperature of the reactionmixture was raised to approximately 77° C. The reaction was deemedcomplete (approximately 13 hours) when <3% of the starting materialremained (in-process high-performance liquid chromatography [HPLC]analysis). The reaction mixture was cooled to approximately 2-7° C. andthen quenched into a chilled solution of dichloromethane (DCM, 482.8kg), 26% NH₄OH (251.3 kg), and water (900 L). The resulting mixture waswarmed to approximately 20-25° C., and phases were separated. Theorganic phase was filtered through a bed of AW hyflo super-cel NF(Celite; 5.4 kg) and the filter bed was washed with DCM (118.9 kg). Thecombined organic phase was washed with brine (282.9 kg) and mixed withwater (120 L). The phases were separated and the organic phase wasconcentrated by vacuum distillation with the removal of solvent(approximately 95 L residual volume). DCM (686.5 kg) was charged to thereactor containing organic phase and concentrated by vacuum distillationwith the removal of solvent (approximately 90 L residual volume). Methylt-butyl ether (MTBE, 226.0 kg) was then charged and the temperature ofthe mixture was adjusted to −20 to −25° C. and held for 2.5 hoursresulting in solid precipitate which was then filtered and washed withn-heptane (92.0 kg), and dried on a filter at approximately 25° C. undernitrogen to afford the title compound. (35.6 kg).

Preparation of 4-(6,7-Dimethoxy-quinoline-4-yloxy)-phenylamine

4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline(35.3 kg), sodium t-butoxide (21.4 kg) and DMA (167.2 kg) at 20-25° C.This mixture was then heated to 100-105° C. for approximately 13 hours.After the reaction was deemed complete as determined using in-processHPLC analysis (<2% starting material remaining), the reactor contentswere cooled at 15 to 20° C. and water (pre-cooled, 2 to 7° C., 587 L)charged at a rate to maintain 15 to 30° C. temperature. The resultingsolid precipitate was filtered, washed with a mixture of water (47 L)and DMA (89.1 kg) and finally with water (214 L). The filter cake wasthen dried at approximately 25° C. on filter to yield crude4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (59.4 kg wet, 41.6 kgdry calculated based on LOD). Crude4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine was refluxed(approximately 75° C.) in a mixture of tetrahydrofuran (THF, 211.4 kg)and DMA (108.8 kg) for approximately 1 h and then cooled to 0-5° C. andaged for approximately 1 h after which time the solid was filtered,washed with THF (147.6 kg) and dried on a filter under vacuum atapproximately 25° C. to yield4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (34.0 kg).

Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid

Triethylamine (19.5 kg) was added to a cooled (approximately 5 C)solution of cyclopropane-1,1-dicarboxylic acid (24.7 kg) in THF (89.6kg) at a rate such that the batch temperature did not exceed 5° C. Thesolution was stirred for approximately 1.3 h, and then thionyl chloride(23.1 kg) was added, keeping the batch temperature below 10 C. When theaddition was complete, the solution was stirred for approximately 4 hkeeping the temperature below 10° C. A solution of 4-fluoroaniline (18.0kg) in THF (33.1 kg) was then added at a rate such that the batchtemperature did not exceed 10 C. The mixture was stirred forapproximately 10 hours after which the reaction was deemed complete. Thereaction mixture was then diluted with isopropyl acetate (218.1 kg).This solution was washed sequentially with aqueous sodium hydroxide(10.4 kg, 50% dissolved in 119 L of water) further diluted with water(415 L), then with water (100 L) and finally with aqueous sodiumchloride (20.0 kg dissolved in 100 L of water). The organic solution wasconcentrated by vacuum distillation (100 L residual volume) below 40° C.followed by the addition of n-heptane (171.4 kg), which resulted in theprecipitation of solid. The solid was recovered by filtration and washedwith n-Heptane (102.4 kg) resulting in wet crude,1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (29.0 kg). Thecrude, 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid wasdissolved in methanol (139.7 kg) at approximately 25° C. followed by theaddition of water (320 L) resulting in slurry which was recovered byfiltration, washed sequentially with water (20 L) and n-heptane (103.1kg) and then dried on the filter at approximately 25 C under nitrogen toafford the title compound (25.4 kg).

Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonylchloride

Oxalyl chloride (12.6 kg) was added to a solution of1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (22.8 kg) in amixture of THF (96.1 kg) and N,N-dimethylformamide (DMF; 0.23 kg) at arate such that the batch temperature did not exceed 25 C. This solutionwas used in the next step without further processing.

Preparation of cyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide

The solution from the previous step containing1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride was added toa mixture of compound 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine(23.5 kg) and potassium carbonate (31.9 kg) in THF (245.7 kg) and water(116 L) at a rate such that the batch temperature did not exceed 30° C.When the reaction was complete (in approximately 20 minutes), water (653L) was added. The mixture was stirred at 20-25 C for approximately 10hours, which resulted in the precipitation of the product. The productwas recovered by filtration, washed with a pre-made solution of THF(68.6 kg) and water (256 L), and dried first on a filter under nitrogenat approximately 25° C. and then at approximately 45 C under vacuum toafford the title compound (41.0 kg, 38.1 kg, calculated based on LOD).

Preparation of cyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide, (L) malate salt

Cyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide (1-5; 13.3 kg), L-malic acid (4.96 kg), methylethyl ketone (MEK; 188.6 kg) and water (37.3 kg) were charged to areactor and the mixture was heated to reflux (approximately 74° C.) forapproximately 2 h. The reactor temperature was reduced to 50 to 55° C.and the reactor contents were filtered. These sequential steps describedabove were repeated two more times starting with similar amounts of 1-5(13.3 kg), L-Malic acid (4.96 kg), MEK (198.6 kg) and water (37.2 kg).The combined filtrate was azeotropically dried at atmospheric pressureusing MEK (1133.2 kg) (approximate residual volume 711 L; KF<0.5% w/w)at approximately 74° C. The temperature of the reactor contents wasreduced to 20 to 25° C. and held for approximately 4 hours resulting insolid precipitate which was filtered, washed with MEK (448 kg) and driedunder vacuum at 50° C. to afford the title compound (45.5 kg).

Example 2 Administration of the compound ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideduring the Concurrent Phase to patients Example 2A

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). The concurrent phase isfollowed by a rest phase that will last for about 4 weeks. TMZ, whengiven, is supplied as 5, 20, 100, 250, 140 and 180 mg dosages (which canbe in capsules or tablets). In another embodiment, the starting dose ofTMZ is 75 mg/m²/day with concurrent RT for 6 weeks. For purposes of thispatent application, the term “m²” refers to body surface area inpatients measured in square meters. Patients receive RT consisting offractional focal irradiation administered using a 1.8-2 Gy/fraction,daily for 5 days/week for 6-7 weeks, for a total dose of up to 60 Gy.

Example 2B

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg dosages (whichcan be in capsules or tablets). The concurrent phase is followed by arest phase that will last for about 4 weeks. TMZ, when given, issupplied as 5 mg dosages (which can be in capsules or tablets). Patientsreceive RT consisting of fractional focal irradiation administered usinga 1.8-2 Gy/fraction, daily for 5 days/week for 6-7 weeks, for a totaldose of up to 60 Gy.

Example 2C

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 50 mg dosages (whichcan be in capsules or tablets). The concurrent phase is followed by arest phase that will last for about 4 weeks. TMZ, when given, issupplied as 5 mg dosages (which can be in capsules or tablets). Patientsreceive RT consisting of fractional focal irradiation administered usinga 1.8-2 Gy/fraction, daily for 5 days/week for 6-7 weeks, for a totaldose of up to 60 Gy.

Example 2D

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 75 mg dosages (whichcan be in capsules or tablets). The concurrent phase is followed by arest phase that will last for about 4 weeks. TMZ, when given, issupplied as 5 mg dosages (which can be in capsules or tablets). Patientsreceive RT consisting of fractional focal irradiation administered usinga 1.8-2 Gy/fraction, daily for 5 days/week for 6-7 weeks, for a totaldose of up to 60 Gy.

Example 2E

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). The concurrent phase isfollowed by a rest phase that will last for about 4 weeks. TMZ, whengiven, is supplied as 5 mg dosages (which can be in capsules ortablets). Patients receive RT consisting of fractional focal irradiationadministered using a 1.8-2 Gy/fraction, daily for 5 days/week for 6-7weeks, for a total dose of up to 60 Gy.

Example 2F

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 100 mg dosages (whichcan be in capsules or tablets). The concurrent phase is followed by arest phase that will last for about 4 weeks. TMZ, when given, issupplied as 20 mg dosages (which can be in capsules or tablets).Patients receive RT consisting of fractional focal irradiationadministered using a 1.8-2 Gy/fraction, daily for 5 days/week for 6-7weeks, for a total dose of up to 60 Gy.

Example 2G

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 50 mg dosages (whichcan be in capsules or tablets). The concurrent phase is followed by arest phase that will last for about 4 weeks. TMZ, when given, issupplied as 20 mg dosages (which can be in capsules or tablets).Patients receive RT consisting of fractional focal irradiationadministered using a 1.8-2 Gy/fraction, daily for 5 days/week for 6-7weeks, for a total dose of up to 60 Gy.

Example 2H

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 75 mg dosages (whichcan be in capsules or tablets). The concurrent phase is followed by arest phase that will last for about 4 weeks. TMZ, when given, issupplied as 20 mg dosages (which can be in capsules or tablets).Patients receive RT consisting of fractional focal irradiationadministered using a 1.8-2 Gy/fraction, daily for 5 days/week for 6-7weeks, for a total dose of up to 60 Gy.

Example 2I

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). The concurrent phase isfollowed by a rest phase that will last for about 4 weeks. TMZ, whengiven, is supplied as 20 mg dosages (which can be in capsules ortablets). Patients receive RT consisting of fractional focal irradiationadministered using a 1.8-2 Gy/fraction, daily for 5 days/week for 6-7weeks, for a total dose of up to 60 Gy.

Example 2J

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 100 mg dosages (whichcan be in capsules or tablets). The concurrent phase is followed by arest phase that will last for about 4 weeks. TMZ, when given, issupplied as 20 mg dosages (which can be in capsules or tablets).Patients receive RT consisting of fractional focal irradiationadministered using a 1.8-2 Gy/fraction, daily for 5 days/week for 6-7weeks, for a total dose of up to 60 Gy.

Example 2K

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg dosages (whichcan be in capsules or tablets). The concurrent phase is followed by arest phase that will last for about 4 weeks. TMZ, when given, issupplied as 100 mg dosages (which can be in capsules or tablets).Patients receive RT consisting of fractional focal irradiationadministered using a 1.8-2 Gy/fraction, daily for 5 days/week for 6-7weeks, for a total dose of up to 60 Gy.

Example 2L

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 50 mg dosages (whichcan be in capsules or tablets). The concurrent phase is followed by arest phase that will last for about 4 weeks. TMZ, when given, issupplied as 100 mg dosages (which can be in capsules or tablets).Patients receive RT consisting of fractional focal irradiationadministered using a 1.8-2 Gy/fraction, daily for 5 days/week for 6-7weeks, for a total dose of up to 60 Gy.

Example 2M

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 75 mg dosages (whichcan be in capsules or tablets). The concurrent phase is followed by arest phase that will last for about 4 weeks. TMZ, when given, issupplied as 100 mg dosages (which can be in capsules or tablets).Patients receive RT consisting of fractional focal irradiationadministered using a 1.8-2 Gy/fraction, daily for 5 days/week for 6-7weeks, for a total dose of up to 60 Gy.

Example 2N

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). The concurrent phase isfollowed by a rest phase that will last for about 4 weeks. TMZ, whengiven, is supplied as 100 mg dosages (which can be in capsules ortablets). Patients receive RT consisting of fractional focal irradiationadministered using a 1.8-2 Gy/fraction, daily for 5 days/week for 6-7weeks, for a total dose of up to 60 Gy.

Example 2O

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 100 mg dosages (whichcan be in capsules or tablets). The concurrent phase is followed by arest phase that will last for about 4 weeks. TMZ, when given, issupplied as 100 mg dosages (which can be in capsules or tablets).Patients receive RT consisting of fractional focal irradiationadministered using a 1.8-2 Gy/fraction, daily for 5 days/week for 6-7weeks, for a total dose of up to 60 Gy.

Example 2P

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg dosages (whichcan be in capsules or tablets). The concurrent phase is followed by arest phase that will last for about 4 weeks. TMZ, when given, issupplied as 140 mg dosages (which can be in capsules or tablets).Patients receive RT consisting of fractional focal irradiationadministered using a 1.8-2 Gy/fraction, daily for 5 days/week for 6-7weeks, for a total dose of up to 60 Gy.

Example 2Q

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 50 mg dosages (whichcan be in capsules or tablets). The concurrent phase is followed by arest phase that will last for about 4 weeks. TMZ, when given, issupplied as 140 mg dosages (which can be in capsules or tablets).Patients receive RT consisting of fractional focal irradiationadministered using a 1.8-2 Gy/fraction, daily for 5 days/week for 6-7weeks, for a total dose of up to 60 Gy.

Example 2R

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 75 mg dosages (whichcan be in capsules or tablets). The concurrent phase is followed by arest phase that will last for about 4 weeks. TMZ, when given, issupplied as 140 mg dosages (which can be in capsules or tablets).Patients receive RT consisting of fractional focal irradiationadministered using a 1.8-2 Gy/fraction, daily for 5 days/week for 6-7weeks, for a total dose of up to 60 Gy.

Example 2S

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). The concurrent phase isfollowed by a rest phase that will last for about 4 weeks. TMZ, whengiven, is supplied as 140 mg dosages (which can be in capsules ortablets). Patients receive RT consisting of fractional focal irradiationadministered using a 1.8-2 Gy/fraction, daily for 5 days/week for 6-7weeks, for a total dose of up to 60 Gy.

Example 2T

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 100 mg dosages (whichcan be in capsules or tablets). The concurrent phase is followed by arest phase that will last for about 4 weeks. TMZ, when given, issupplied as 140 mg dosages (which can be in capsules or tablets).Patients receive RT consisting of fractional focal irradiationadministered using a 1.8-2 Gy/fraction, daily for 5 days/week for 6-7weeks, for a total dose of up to 60 Gy.

Example 2U

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg dosages (whichcan be in capsules or tablets). The concurrent phase is followed by arest phase that will last for about 4 weeks. TMZ, when given, issupplied as 180 mg dosages (which can be in capsules or tablets).Patients receive RT consisting of fractional focal irradiationadministered using a 1.8-2 Gy/fraction, daily for 5 days/week for 6-7weeks, for a total dose of up to 60 Gy.

Example 2V

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 50 mg dosages (whichcan be in capsules or tablets). The concurrent phase is followed by arest phase that will last for about 4 weeks. TMZ, when given, issupplied as 180 mg dosages (which can be in capsules or tablets).Patients receive RT consisting of fractional focal irradiationadministered using a 1.8-2 Gy/fraction, daily for 5 days/week for 6-7weeks, for a total dose of up to 60 Gy.

Example 2W

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 75 mg dosages (whichcan be in capsules or tablets). The concurrent phase is followed by arest phase that will last for about 4 weeks. TMZ, when given, issupplied as 180 mg dosages (which can be in capsules or tablets).Patients receive RT consisting of fractional focal irradiationadministered using a 1.8-2 Gy/fraction, daily for 5 days/week for 6-7weeks, for a total dose of up to 60 Gy.

Example 2X

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). The concurrent phase isfollowed by a rest phase that will last for about 4 weeks. TMZ, whengiven, is supplied as 180 mg dosages (which can be in capsules ortablets). Patients receive RT consisting of fractional focal irradiationadministered using a 1.8-2 Gy/fraction, daily for 5 days/week for 6-7weeks, for a total dose of up to 60 Gy.

Example 2Y

N-(4-{[6,7-bis(methyoxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 100 mg dosages (whichcan be in capsules or tablets). The concurrent phase is followed by arest phase that will last for about 4 weeks. TMZ, when given, issupplied as 180 mg dosages (which can be in capsules or tablets).Patients receive RT consisting of fractional focal irradiationadministered using a 1.8-2 Gy/fraction, daily for 5 days/week for 6-7weeks, for a total dose of up to 60 Gy.

Example 2Z

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg dosages (whichcan be in capsules or tablets). The concurrent phase is followed by arest phase that will last for about 4 weeks. TMZ, when given, issupplied as 250 mg dosages (which can be in capsules or tablets).Patients receive RT consisting of fractional focal irradiationadministered using a 1.8-2 Gy/fraction, daily for 5 days/week for 6-7weeks, for a total dose of up to 60 Gy.

Example 2AA

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 50 mg dosages (whichcan be in capsules or tablets). The concurrent phase is followed by arest phase that will last for about 4 weeks. TMZ, when given, issupplied as 250 mg dosages (which can be in capsules or tablets).Patients receive RT consisting of fractional focal irradiationadministered using a 1.8-2 Gy/fraction, daily for 5 days/week for 6-7weeks, for a total dose of up to 60 Gy.

Example 2AB

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluoropheny)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 75 mg dosages (whichcan be in capsules or tablets). The concurrent phase is followed by arest phase that will last for about 4 weeks. TMZ, when given, issupplied as 250 mg dosages (which can be in capsules or tablets).Patients receive RT consisting of fractional focal irradiationadministered using a 1.8-2 Gy/fraction, daily for 5 days/week for 6-7weeks, for a total dose of up to 60 Gy.

Example 2AC

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). The concurrent phase isfollowed by a rest phase that will last for about 4 weeks. TMZ, whengiven, is supplied as 250 mg dosages (which can be in capsules ortablets). Patients receive RT consisting of fractional focal irradiationadministered using a 1.8-2 Gy/fraction, daily for 5 days/week for 6-7weeks, for a total dose of up to 60 Gy.

Example 2AD

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis initiated at the start of a 6-7 week concurrent phase of RT and TMZ.Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 100 mg dosages (whichcan be in capsules or tablets). The concurrent phase is followed by arest phase that will last for about 4 weeks. TMZ, when given, issupplied as 250 mg dosages (which can be in capsules or tablets).Patients receive RT consisting of fractional focal irradiationadministered using a 1.8-2 Gy/fraction, daily for 5 days/week for 6-7weeks, for a total dose of up to 60 Gy.

Example 3 Administration of the compound ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideduring the Concurrent Phase to patients Example 3A

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as 25 mg and 100 mg dosages (which can be in capsules ortablets). Some patients that have a mutation in the MGMT promoter,wherein the mutated MGMT promoter is an unmethylated promoter, may notreceive TMZ and instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). TMZ, when given, issupplied as 5, 20, 100, 250, 140, 180, and 200 mg dosages (which can bein capsules or tablets) given for 5 consecutive days and repeated every28 days. In another embodiment, TMZ is administered in the amount of 200mg/m²/day given for 5 consecutive days and repeated every 28 days. Forpurposes of this disclosure, the term m² is meant to mean body surfacearea in patients measured in square meters. The maintenance phase inExample 3A can be combined with the concurrent phase of any of Examples2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R,2S, 2T, 2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.

Example 3B

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as 25 mg dosages (which can be in capsules or tablets).Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). TMZ, when given, issupplied as 5 mg dosages (which can be in capsules or tablets) given for5 consecutive days and repeated every 28 days. The maintenance phase inExample 3B can be combined with the concurrent phase of any of Examples2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R,2S, 2T, 2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.

Example 3C

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as 50 mg dosages (which can be in capsules or tablets).Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). TMZ, when given, issupplied as 5 mg dosages (which can be in capsules or tablets) given for5 consecutive days and repeated every 28 days. The maintenance phase inExample 3C can be combined with the concurrent phase of any of Examples2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R,2S, 2T, 2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.

Example 3D

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as 75 mg dosages (which can be in capsules or tablets).Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). TMZ, when given, issupplied as 5 mg dosages (which can be in capsules or tablets) given for5 consecutive days and repeated every 28 days. The maintenance phase inExample 3D can be combined with the concurrent phase of any of Examples2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R,2S, 2T, 2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.

Example 3E

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as 100 mg dosages (which can be in capsules or tablets).Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). TMZ, when given, issupplied as 5 mg dosages (which can be in capsules or tablets) given for5 consecutive days and repeated every 28 days. The maintenance phase inExample 3E can be combined with the concurrent phase of any of Examples2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R,2S, 2T, 2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.

Example 3F

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as 25 mg dosages (which can be in capsules or tablets).Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). TMZ, when given, issupplied as 20 mg dosages (which can be in capsules or tablets) givenfor 5 consecutive days and repeated every 28 days. The maintenance phasein Example 3F can be combined with the concurrent phase of any ofExamples 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P,2Q, 2R, 2S, 2T, 2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.

Example 3G

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as 50 mg dosages (which can be in capsules or tablets).Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). TMZ, when given, issupplied as 20 mg dosages (which can be in capsules or tablets) givenfor 5 consecutive days and repeated every 28 days. The maintenance phasein Example 3G can be combined with the concurrent phase of any ofExamples 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P,2Q, 2R, 2S, 2T, 2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 82AD.

Example 3H

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as 75 mg dosages (which can be in capsules or tablets).Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). TMZ, when given, issupplied as 20 mg dosages (which can be in capsules or tablets) givenfor 5 consecutive days and repeated every 28 days. The maintenance phasein Example 3H can be combined with the concurrent phase of any ofExamples 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P,2Q, 2R, 2S, 2T, 2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.

Example 3I

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as 100 mg dosages (which can be in capsules or tablets).Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). TMZ, when given, issupplied as 20 mg dosages (which can be in capsules or tablets) givenfor 5 consecutive days and repeated every 28 days. The maintenance phasein Example 3I can be combined with the concurrent phase of any ofExamples 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P,2Q, 2R, 2S, 2T, 2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.

Example 3J

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as 25 mg dosages (which can be in capsules or tablets).Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). TMZ, when given, issupplied as 100 mg dosages (which can be in capsules or tablets) givenfor 5 consecutive days and repeated every 28 days. The maintenance phasein Example 3J can be combined with the concurrent phase of any ofExamples 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P,2Q, 2R, 2S, 2T, 2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.

Example 3K

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as 50 mg dosages (which can be in capsules or tablets).Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). TMZ, when given, issupplied as 100 mg dosages (which can be in capsules or tablets) givenfor 5 consecutive days and repeated every 28 days. The maintenance phasein Example 3K can be combined with the concurrent phase of any ofExamples 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P,2Q, 2R, 2S, 2T, 2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.

Example 3L

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as 75 mg dosages (which can be in capsules or tablets).Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). TMZ, when given, issupplied as 100 mg dosages (which can be in capsules or tablets) givenfor 5 consecutive days and repeated every 28 days. The maintenance phasein Example 3L can be combined with the concurrent phase of any ofExamples 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P,2Q, 2R, 2S, 2T, 2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.

Example 3M

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as 100 mg dosages (which can be in capsules or tablets).Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). TMZ, when given, issupplied as 100 mg dosages (which can be in capsules or tablets) givenfor 5 consecutive days and repeated every 28 days. The maintenance phasein Example 3M can be combined with the concurrent phase of any ofExamples 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P,2Q, 2R, 2S, 2T, 2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.

Example 3N

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as 25 mg dosages (which can be in capsules or tablets).Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). TMZ, when given, issupplied as 140 mg dosages (which can be in capsules or tablets) givenfor 5 consecutive days and repeated every 28 days. The maintenance phasein Example 3N can be combined with the concurrent phase of any ofExamples 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P,2Q, 2R, 2S, 2T, 2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.

Example 30

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as 50 mg dosages (which can be in capsules or tablets).Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). TMZ, when given, issupplied as 140 mg dosages (which can be in capsules or tablets) givenfor 5 consecutive days and repeated every 28 days. The maintenance phasein Example 30 can be combined with the concurrent phase of any ofExamples 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P,2Q, 2R, 2S, 2T, 2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.

Example 3P

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as 75 mg dosages (which can be in capsules or tablets).Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). TMZ, when given, issupplied as 140 mg dosages (which can be in capsules or tablets) givenfor 5 consecutive days and repeated every 28 days. The maintenance phasein Example 3P can be combined with the concurrent phase of any ofExamples 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P,2Q, 2R, 2S, 2T, 2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.

Example 30

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as 100 mg dosages (which can be in capsules or tablets).Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). TMZ, when given, issupplied as 140 mg dosages (which can be in capsules or tablets) givenfor 5 consecutive days and repeated every 28 days. The maintenance phasein Example 3Q can be combined with the concurrent phase of any ofExamples 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P,2Q, 2R, 2S, 2T, 2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.

Example 3R

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as 25 mg dosages (which can be in capsules or tablets).Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). TMZ, when given, issupplied as 180 mg dosages (which can be in capsules or tablets) givenfor 5 consecutive days and repeated every 28 days. The maintenance phasein Example 3R can be combined with the concurrent phase of any ofExamples 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P,2Q, 2R, 2S, 2T, 2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.

Example 3S

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as 50 mg dosages (which can be in capsules or tablets).Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). TMZ, when given, issupplied as 180 mg dosages (which can be in capsules or tablets) givenfor 5 consecutive days and repeated every 28 days. The maintenance phasein Example 3S can be combined with the concurrent phase of any ofExamples 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P,2Q, 2R, 2S, 2T, 2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.

Example 3T

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as 75 mg dosages (which can be in a capsule or tablet).Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). TMZ, when given, issupplied as 180 mg dosages (which can be in capsules or tablets) givenfor 5 consecutive days and repeated every 28 days. The maintenance phasein Example 3T can be combined with the concurrent phase of any ofExamples 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P,2Q, 2R, 2S, 2T, 2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.

Example 3U

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as 100 mg dosages (which can be in capsules or tablets).Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). TMZ, when given, issupplied as 180 mg dosages (which can be in capsules or tablets) givenfor 5 consecutive days and repeated every 28 days. The maintenance phasein Example 3U can be combined with the concurrent phase of any ofExamples 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P,2Q, 2R, 2S, 2T, 2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.

Example 3V

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as 25 mg dosages (which can be in capsules or tablets).Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). TMZ, when given, issupplied in doses of 200 mg/m²/day given for 5 consecutive days andrepeated every 28 days. The maintenance phase in Example 3V can becombined with the concurrent phase of any of Examples 2A, 2B, 2C, 2D,2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T, 2U, 2V,2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.

Example 3W

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as 50 mg dosages (which can be in capsules or tablets).Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). TMZ, when given, issupplied in doses of 200 mg/m²/day given for 5 consecutive days andrepeated every 28 days. The maintenance phase in Example 3W can becombined with the concurrent phase of any of Examples 2A, 2B, 2C, 2D,2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T, 2U, 2V,2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.

Example 3X

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as 75 mg dosages (which can be in capsules or tablets).Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). TMZ, when given, issupplied in doses of 200 mg/m²/day given for 5 consecutive days andrepeated every 28 days. The maintenance phase in Example 3X can becombined with the concurrent phase of any of Examples 2A, 2B, 2C, 2D,2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T, 2U, 2V,2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.

Example 3Y

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as 100 mg dosages (which can be in capsules or tablets).Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). TMZ, when given, issupplied in doses of 200 mg/m²/day given for 5 consecutive days andrepeated every 28 days. The maintenance phase in Example 3Y can becombined with the concurrent phase of any of Examples 2A, 2B, 2C, 2D,2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T, 2U, 2V,2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.

Example 3Z

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as 25 mg dosages (which can be in capsules or tablets).Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). TMZ, when given, issupplied as 250 mg dosages (which can be in capsules or tablets) givenfor 5 consecutive days and repeated every 28 days. The maintenance phasein Example 3Z can be combined with the concurrent phase of any ofExamples 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P,2Q, 2R, 2S, 2T, 2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.

Example 3AA

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as 50 mg dosages (which can be in capsules or tablets).Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). TMZ, when given, issupplied as 250 mg dosages (which can be in capsules or tablets) givenfor 5 consecutive days and repeated every 28 days. The maintenance phasein Example 3AA can be combined with the concurrent phase of any ofExamples 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P,2Q, 2R, 2S, 2T, 2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.

Example 3AB

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as 75 mg dosages (which can be in capsules or tablets).Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). TMZ, when given, issupplied in doses of 200 mg/m²/day given for 5 consecutive days andrepeated every 28 days. The maintenance phase in Example 3AB can becombined with the concurrent phase of any of Examples 2A, 2B, 2C, 2D,2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T, 2U, 2V,2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.

Example 3AC

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as 100 mg dosages (which can be in capsules or tablets).Some patients that have a mutation in the MGMT promoter, wherein themutated MGMT promoter is an unmethylated promoter, may not receive TMZand instead receiveN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a single agent in combination with RT.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis administered as a single oral agent supplied as 25 mg and 100 mgdosages (which can be in capsules or tablets). TMZ, when given, issupplied as 250 mg dosages (which can be in capsules or tablets) givenfor 5 consecutive days and repeated every 28 days. The maintenance phasein Example 3AC can be combined with the concurrent phase of any ofExamples 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P,2Q, 2R, 2S, 2T, 2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.

The foregoing disclosure has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications can be made while remainingwithin the spirit and scope of the invention. It will be obvious to oneof skill in the art that changes and modifications can be practicedwithin the scope of the appended claims. Therefore, it is to beunderstood that the above description is intended to be illustrative andnot restrictive. The scope of the invention should, therefore, bedetermined not with reference to the above description, but shouldinstead be determined with reference to the following appended claims,along with the full scope of equivalents to which such claims areentitled.

What is claimed is:
 1. A method of treating cancer, wherein the methodcomprises administering to a patient in need of the treatment a compoundof Formula I:

or a pharmaceutically acceptable salt thereof, in combination withtemozolomide (TMZ) wherein: R¹ is halo; R² is halo; and Q is CH or N. 2.A method of treating cancer, wherein the method comprises administeringto a patient in need of the treatment a compound of Formula I:

or a pharmaceutically acceptable salt thereof, in combination withradiation therapy (RT) wherein: R¹ is halo; R² is halo; and Q is CH orN.
 3. The method according to any of claims 1-2, wherein the compound ofFormula I is represented by the following structure:

or a pharmaceutically acceptable salt thereof.
 4. The method accordingto any one of claims 1-2, wherein the compound of Formula I isrepresented by the following structure:


5. The method according to any one of claims 1-3, wherein the compoundof Formula I, or a pharmaceutically acceptable salt thereof, furthercomprises a pharmaceutically acceptable carrier, excipient, or diluent.6. The method according to according to any one of claims 1 and 3-5,wherein the one or more additional treatment(s) are selected from (1)surgery, (2) one or more additional chemotherapeutic agent(s), (3) oneor more hormone therapy(s), (4) one or more antibody(s), (5) one or moreimmunotherapy(ies), (6) radioactive iodine therapy, and (7) radiation.7. The method according to any one of claims 1 and 3-6, wherein the oneor more additional treatment(s) is radiation.
 8. The method according toany one of claims 1-7 comprising administering a therapeuticallyeffective dose of compound (I) or a pharmaceutically acceptable saltthereof.
 9. The method according to any one of claims 1 and 3-8comprising administering a therapeutically effective dose of TMZ. 10.The method according to any one of claims 2-9 comprising administering atherapeutically effective dose of radiation.
 11. The method according toany one of claims 1-10, where the cancer is brain cancer.
 12. The methodaccording to any one of claims 1-11, where the cancer is selected fromastocytoma, glioblastoma, giant cell glioblastoma, gliosarcoma, andglioblastoma with oligodendroglial components.
 13. The method accordingto any one of claims 1-12, wherein the method comprises (1) a concurrentphase, (2) a rest phase and (3) a maintenance phase, wherein: theconcurrent phase comprises administering radiation and the compound ofFormula I to the patient; the rest phase comprises not administering thecompound of Formula I or radiation to the patient; and the maintenancephase comprises administering the compound of Formula I to the patient.14. The method according to any one of claims 1-13, wherein theconcurrent phase is 7-8 weeks in duration, and the rest phase is about 4weeks in duration; and the maintenance phase is of a duration sufficientslow down the cancer growth.
 15. The method according to any one ofclaims 1-14, wherein the compound of Formula I is administered to thepatient in 25-125 mg dosages daily during the concurrent phase; TMZ isadministered to the patient in 5-180 mg dosages daily to the patientduring the concurrent phase; RT is administered to the patient duringthe concurrent phase using 1.8-2 Gy/fraction, daily for 5 days/week fora total dose of up to 60 Gy; the compound of Formula I is administeredto the patient in 25-125 mg dosages daily during the maintenance phase;and TMZ is administered to the patient in 5-180 mg dosages for 5consecutive days and repeated every 28 days until the cancer growth isslowed down.